Document JR6LxmEYZ8y2qaDGR1oOMqYr

Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Hodgkin's Disease: Current Recommendations for Management Henry S. Kaplan and Saul A. Rosenberg CA Cancer J Clin 1975;25;306-319 DOI: 10.3322/canjclin.25.6.306 This information is current as of May 14, 2010 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://caonline.amcancersoc.org To subscribe to the print issue of CA: A Cancer Journal for Clinicians, go to (US individuals only): http://caonline.amcancersoc.org/subscriptions/ CA: A Cancer Journal for Clinicians is published six times per year for the American Cancer Society by Wiley-Blackwell. A bimonthly publication, it has been published continuously since November 1950. CA is owned, published, and trademarked by the American Cancer Society, 250 Williams Street NW, Atlanta GA 30303. (American Cancer Society, Inc.) All rights reserved. Print ISSN: 0007-9235. Online ISSN: 1542-4863. Hodgkin's Disease: current Recommen is for Management Henry S. Kaplan, M.D. and Saul A. Rosenberg, M.D. Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Since 1962, we have conducted a series of controlled clinical trials at Stanford University Medical Center aimed at op timizing the treatment of Hodgkin's dis ease. Design, eligibility criteria and in terim results have been previously re ported. 1-3These and other clinical stud ies will undoubtedly continue to provide substantial additional information as more cases are accrued and observed for longer follow-up periods. However, the fact that certain aspects of treatment are in a state of flux creates difficulties for the practicing physician called on to manage a patient with Hodgkin's dis ease. This article sets forth a distillation of our current views concerning optimal management in relation to site(s) and stage of disease, constitutional symp toms and histopathology, both for the previously untreated patient and also for the previously treated, relapsing patient who poses a much more difficult prob lem. In most instances, recom Dr. Kaplan is Maureen Lyles D'Ambrogio Profes sor of Radiology and Director, Cancer Biology Research Laboratory, Department of Radiology, Stanford University Medical Center, Stanford, Cal ifornia. Dr. Rosenberg is Chief, Division of Medical On cology, and Professor of Medicine and Radiology, Stanford University Medical Center, Stanford, Cal ifornia. Presented in part at the American Cancer Soci ety/National Cancer Institute's National Conference on Advances in Cancer Management, Part I: Treat ment and Rehabilitation, New York City, No vember 25-27, 1974. Adapted from: Kaplan, H.S., and Rosenberg, S.A.: The management of Hodgkin's disease. Cancer 36:796-803, 1975. mendations are based on the results of our clinical trials, but in some situations where definitive data are not yet avail able, we have relied on our best clinical judgment at this time. Diagnostic Evaluation Nearly 10 years of field testing have provided convincing evidence that the Rye histopathological classification does indeed correlate well with prognosis.4 Although most cases can be readily classified among the four categories described in Table 1, approximately 15 percent of patients present with features that make classification difficult; when therapeutic management depends on the outcome, consultation, preferably with hematopathologists, should be sought. Although it is usually both feasible and desirable to complete the diagnostic workup (Table 2.) before undertaking treatment, not infrequently a modified approach is indicated.5 For example, the patient with massive mediastinal and/or hilar lymphadenopathy is not a good candidate for either lymphangiography or staging laparotomy until the thoracic lymph node masses have been apprecia bly reduced in size. This is accom plished by first delivering part of the planned course of mantle field radio therapy (1500-2000 rads in two-two and a half weeks) and then performing the lymphangiogram and staging laparo tomy during a planned 10-14 day inter ruption of treatment. The final treatment 306 CA"ACANCERJOURNALFORCLINICIANS Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Type Lymphocyte predominance (LP) Nodular sclerosis (NS) Mixed cellularity (MC) Table 1. Histopathological Classification* Features Abundant lymphocytic stroma; sparse Reed-Sternberg (R"S) cells.* * Nodules of lymphoid tissue of varying size,separatedby bandsof collagenand con taining oelacucneallr variants of R"Scells. More numerous R"Scells in pleomorphic stroma rich in eosinophils, plasmacells, fibroblasts and lymphocytes. Relative Prognosis Most favorable Favorable Guarded Lymphocyte depletion (LD) Paucity of lymphocytes; diffuse, irregular fibrosis in some instances;bizarre, anaplastic R"Scells usually flu merous. Least favorable * Rye classification.4 **RS cells are essentialfor diagnosisof Hodgkin's disease,but are not pathognomonic; they may be seenin infectious mononucleosis, metastatic breast cancer,etc. It is therefore important to observethem in an appropriate stroma. I plan is outlined only after the extent of subdiaphragmatic disease has been dis closed by these procedures.@ When mantle field treatment is resumed, new lead shielding blocks are prepared to provide greater protection for the lungs, while tightly matching the reduced me diastinal/hilar adenopathy silhouette. Intravenous urograms, upper GI series, barium enemas and liver-spleen scans have been omitted from the routine diag nostic workup since they have too low a yield in Hodgkin's disease. These pro cedures should, therefore, be added se lectively when specifically indicated by the patient's symptomatology. Clinical Staging The Ann Arbor Clinical Staging Clas sification adopted in 1971 has proven to be a practical and workable scheme .@ (Table 3.) It distinguishes between the Clinical Stage (CS), determined by ini tial biopsy, history and physical exami nation, laboratory tests and radiographic evidence, and the Pathological Stage (PS), which adds additional definitive histopathologic information obtained at staging laparotomy, exploratory thora cotomy and/or bone marrow biopsy. VOL 25, NO 6 NOVEMBER/DECEMB1E9R75 307 Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 2. Diagnostic Work-up A. Careful history, with special attention to unexplained fever, night sweats, weight loss of more than 10 percent in prior 6 months. B. Physical examination, emphasizing peripheral lymph node chains, liver, spleen and bony tenderness. C. Chest roentgenogram; whole-lung tomography if mediastinal/hilar adenopathy present. D. Bilateral lower extremity lymphangiography; identification of suspicious nodes. E. Laboratory tests, especially CBC and platelet count, serum alkaline phosphatase, ESR and serum Cu++. F. Staging laparotomy (except when Stage IV disease is apparent); splenectomy and biopsy of suspicious para-aortic, celiac, porta hepatis, splenic hilar and/or iliac nodes, liver, and iliac crest bone marrow.5 @ G. Radioisotopic scans (optional): 67Ga, 99mTcEHDP, 1lnCl3. H. Delayed hypersensitivity skin tests (optional): natural intradermal antigens, DNCB. Biopsy-proven lesions of the liver or bone marrow are invariably defined as Stage IV disease. Lesions of other extra lymphatic tissues, such as the lung, pleura or bone, must be judged individ ually: they may be either oeElesions, if localized, or Stage IV disease, if mul tiple or disseminated. Radiotherapy The oecardinafleatures of modern radiotherapy for Hodgkin's disease with curative intent are set forth in Table 4. The technical aspects have been fully detailed elsewhere.8 The use of small 60 Co teletherapy units, operating at treatment distances of 80 cm. or less, results in a patchwork quilt of small treatment fields which invite frequent technical errors. The patient with pre viously untreated, potentially curable Hodgkin's disease deserves optimal treatment the first time. When the requi site equipment and/or radiotherapeutic expertise are not available in his com munity, the patient should be referred to the nearest major medical center for high precision radiotherapy. A number of radiotherapeutic field distributions are now available to deal flexibly with a va riety of clinical presentations. (Tables 5. and 6.) Chemotherapy The number of chemotherapeutic agents with demonstrated therapeutic ef ficacy in Hodgkin's disease has been growing rapidly in recent years. (Table 7.) Significantly, the sites of major tox icity of these agents are not all the same; although most are myelotoxic, some pri marily effect the nervous system or gas 308 CA--A CANCERJOURNALFORCLINICIANS Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 3. Clinical Staging Classification* Stage Definition Involvement of a single lymph node region (I) or of a single extralymphatic organ or site Involvement of two or more lymph node regions on the same side of the II diaphragm (II) or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (E) Involvement of lymph node regions on both sides of the diaphragm (III), III which may also be accompanied by involvement of the spleen (llI@) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIISE). Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement. The presence or absence of fever, night sweats and/or unexplained loss of 10 percent or more of body weight in the six months preceding admission are denoted by the suffix letters B and A, respectively. Biopsy"documented involvement of Stage IV sites is also denoted by letter suffixes: marrow = M+; lung = L+; liver = H+; pleura = P+; bone = 0+; skin and subcutaneous tissue = D+. *Adopted at the workshop on the Staging of Hodgkin's Disease held at Ann Arbor, Michigan, April, 1971.@ @I .-A.Tumoricidal Radiotherapy: Cardinal Features ~. .- dose: 3,500 rads/3.5 weeks to 4,400 rads/4 weeks; local oebootsot 5,000 rads/5-6 weeks to exceptionally large or slowly regressing lymph node masses.B.Large fields: Shaped to encompass multiple lymph node chains (anterior and Waldeypeor)s.Cte.rMioergaovpopltoasgeed, except for beam energies: Linear accelerator or 60Co teletherapy apparatus with treatment distance capability of 100"140cm. VOL 25 NO 6 NOVEMBER/DECEMBER 1975 309 Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 5. RadiotherapyFields Mantle Encompasses mediastinal, hilar, and bilateral supraclavicular, infraclavicular, cervical, and axillary node chains, with lead shields shaped to lungs, heart, spinal cord (after 2,000 rads).8 lnverted"Y Encompassesplenic or splenic pedicle, para-aortic iliac, inguinal, and femoral node chains, with lead shields for rectum and bladder, iliac and upper femoral bone marrow, and oegaatpjunction with mantle field;8 Or Spade Encompasses splenic or splenic pedicle, para-aortic and common iliac node chains, with double thickness lead shields for gonads and pelvic structures; Or Para-aortic/hepatic Encompasses splenic hilar and para-aortic node chains and entire right lobe of liver (through 50 percent transmission lead block), usually joined across another oegap by a separate pelvic field.9 Pelvic field Encompasses external iliac, inguinal, andfemoral node chains, with lead shields for rectum and bladder, iliac, and upper femoral bone marrow. oeWaldeyer Opposed lateral fields, encompasses pre-auricular nodes and lymphatic tissues of Waldeyer's ring when clinically involved or when adenopathy present in high cervical nodes. / trointestinal tract. Thus, modern combi Treatment of the Previously nation chemotherapy regimens (Table Untreated Patient 8.) seek to obtain the additive antitumor Our treatment recommendations for effects of three or more agents with non patients with previously untreated overlapping normal tissue toxicities. At Hodgkin's disease are based on a graded present, MOPP and its British variant, sequence of options related to stage, MVPP, are the most firmly established symptoms, histopathology and present programs, but a number of other four ing site. (Table 9.) Local, involved-field and five-drug regimens are currently or limited radiotherapy still has a valid under investigation. Management of the place in the management of certain patient who relapses after an adequate Stage IA and hA presentations (Table 9, trial of MOPP chemotherapy has been situations 1-3), and subtotal radio a particularly distressing problem. The therapy in others (Table 9, situations 4 recent, highly encouraging oecrossover and 5). For more extensive or sympto experience with the ABVD and CAVe matic Stage II disease, or in patients regimens may provide at least a partial with unfavorable histologic patterns, solution to this problem. however, total lymphoid radiotherapy 310 CA"A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Split coursetreatment of very large mediastinal massesn; ormally 1,500"2,00r0ads/2 weeks, then 1"2week interruption to permit regression (and staging laparotomy), followed by resumption and completion of mantle field radiotherapy with reduced mediastinaalperture. Thin lung(30 percentransmissionb)locks overoneor both lungswhenhilar adeno pathy present, to deliver: 1,600 rads/4 weeks to entire lung.1 0 Subcarinal blocks, added across lower mediastinal field, from about 5 cm. below carina down to diaphragm, to shield heart after dose of 3,000"3,500rads has been deliveretdo the mantlefield. Horizontadl ecubituuspperabdominafileldsforopposeldateralportirradiationof para-aortic and mesenteric nodes with kidneys shielded. Minimantle field, similar to the mantle, but with the mediastinum and hilar regions shieldedt;hus,both supraclaviculacre,rvicali,nfraclaviculaanrd, axillarnyode chains aretreated. p must now be regarded as the treatment sion has been attained, have come into of choice, either alone or supplemented use in many Stage IV situations (Table by six cycles of MOP combination 9, situations 11-13). Such combined chemotherapy (Table 9, situations 6-8). chemotherapy-radiotherapy programs In Stage 1115Awith documented involve are formidable, and should be used se ment of the spleen by NS or LP type lectively in relatively young patients disease, total lymphoid radiotherapy who are in good general health, reserv may be optionally supplemented with ei ing chemotherapy alone for elderly pa ther hepatic irradiation (2200 rads/four tients and those in frail condition. weeks) or six cycles of MOP chemo therapy;'6 in the presence of consti tutional symptoms and/or unfavorable Treatment of the Previously Treated Patient in Relapse histology, both hepatic irradiation and The nature and extent of previous MOP chemotherapy are added to total treatment influences and often severely lymphoid radiotherapy. Patients with limits the treatment of relapsing disease. Stage IV disease usually require combi Nonetheless, modern treatment modali nation chemotherapy as the mainstay of ties make possible a very gratifying rate their management, but those treated of salvage, especially in first relapses. with chemotherapy alone have a rela When the full extent of disease is not tively high rate of relapse in sites of ini apparent at the time of first relapse, a tially bulky lymphadenopathy. Hence, complete diagnostic workup should be strategies which incorporate moderate performed, including a repeat lymphan dose radiotherapy either in a oesplit giogram and, if necessary, laparotomy course approach or at the end of mul with splenectomy and biopsies of para tiple drug cycles, when complete remis aortic nodes, liver and marrow. The VOL 25. NO 6 NOVEMBER/DECEMBER 1975 311 Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 7. SingleAgent Chemotherapy: Palliation in Advanced,RelapsingDisease Agent UsualDose Route,Interval Mechanism of Action Major Toxicity Nitrogen mustard (Mustargen, HN2) 0.4 mg./kg., IV every 4"8weeks Alkylation Bone marrow, nausea, vomiting Chlorambucil (Leukeran,CLB) 0.1"0.2mg./kg./day, P.O. Alkylation Bone marrow Cyclophosphamide (Cytoxan, CTX)50"200 nauseaVinblastine mg./day, P.O. or 20"40mg./kg., IV every 3"4weeksBone Alkylation marrow, cystitis, alopecia, mg./m.2,IV (pVoeilsboannG,rVaLnBu)l3ocy"t6openiaVeivnecrryi1sti"nw2eeeksMitotic spindle (Oncovin, VCR)1"1.4 mg./m.2, IV every 1"2weeksMitotic spindle poisonNeuropathy Procarbaznie (Natulan,Matulane PCB) 50-250 mg./day, P.O. Alkylation, oxidation? Bone marrow, nausea, vomiting Adriamycin mg./m.2, IV (ADM)25"80 every 3"4weeksAntibiotic, intercalation cardiomyopathyAnaphylactoidBleomycin into DNABone marrow, alopecia, (BLM)2.5-15 fibrosisNitrosoureas (BCNU, CCNU)70"1 Di methyl-triazeno mi dazole-carboxam ide (DTIC) Corticostreoids (Prednisone) mg./m.2, IV every weekAntibioticand 30 mg./m.2 for 1"d2ays (IV,P.O.)AlkylationBone 150-200 mg./m.2, IV for 4"5days An timetabolite? Variable, P.O. Ly mpholy tic febrile reac tions, pulmonary marrow Gastrointestinal, bone marrow Cushing's syn drome proper course of action cannot be arrived at without objective knowledge of the distribution of relapsing sites of disease. Treatment of relapses in lymph nodes, spleen or localized osseous or subcutan eous sites in patients previously treated with radiotherapy only (Table 10, situa tions 1-5 and 10) calls for high dose radiotherapy to the site(s) of relapse and previously untreated lymphoid regions. supplemented in most instances by six cycles of MOP chemotherapy. Relapses in liver, lung, bone marrow or multiple, disseminated sites in patients previously 312 CA"A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 8. Combination Chemotherapy Regimens oeMOPP11 HN2 VC R PCB PRD 6 mg./m.2, IV, days 1 & 8 1.0"1m.g4./m.2,IV,days 1 & 8 100 mg./m.2/day,P.O.,days 1"14 40 mg./m.2/day,P.O.,days 1-14 14"dacyyclesseparatedby 14"daryestperiods;usually6 or more cycles;PRD in cycles 1 & 4 only. oeMVP2 P1 HN2 VLB PCB PRD 6 mg./m.2, IV, days 1 & 8 6 mg./m.2, IV, days 1 & 8 100 mg./m.2, P.O., days 1-14 40 mg./day, P.O., days 1"14 14"daycycles separated by 28"dayrest periods; usually 6 or more cycles; PRD given in all cycles. oeAB1V3D ADM BLM VLB DTIC 25 mg./m.2, IV, days 1 & 14 10 mg./m.2, IV, days 1 & 14 6 mg./m.2, IV, days 1 & 14 150 mg./m.2, IV, days 1"5 14"daycycles and 14"dayrest periods. Advantage: no cross-resistance vs. MOPP; highrateof responseinMOPP failure(s~"75per"c8e0nt). oeCAVe14 CCN U ADM VLB 100 mg./m.2, P.O., day 1 60 mg./m.2, IV, day 1 Smg./m.2,IV, day1 Cycles repeated every 6 weeks (if blood counts permit) to total of 9 cycles; about 50 percent response rate in MOPP failures. oeMOP Same as MOPP, except for the omission of prednisone in all cycles in patients previously treated with mantle field radiotherapy.15 treated with radiotherapy only. are best managed with MOP chemotherapy (six or more cycles), optionally supple mented in some instances with low to moderate dose radiotherapy to the site(s) of relapse (Table 10. situations 6, 8 and 9). Patients who relapse following single-drug chemotherapy are often moderately to severely cytopenic and have limited tolerance for combination chemotherapy; in general. the regimen selected for these patients should be comprised of agents that have not yet produced resistance. Patients who de VOL 25. NO 6 NOVEMBER/DECEMBER 1975 313 Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 9. Therapeutic Recommendations for Previously Untreated Patients Clinical Situation 1. Stage PS IA (LP or NS type) limited to one upper cervicarlegion,with negative lymphangiogram and laparotomy. Recommended Treatment Ipsilateral local cervical-supra clavicular or minimantle and Waldeyer field radiotherapy only. 2. StageCS IA (NS type)limitedto the mediastinal region, with clinically nega tive hilar and cervical-supraclavicular nodes and negative lymphangiogram (laparotomy optional). Mantle field radiotherapy only. 3. StagesPS IA (LPor NS type)limitedto one inguinal/femorarlegion,with negativelymph angiogramand laparotomy. Inverted"V (pelvis, para-aortic, and splenic pedicle) field radio therapy only. 4a. StagePS IA (LP or NS type)involvinogne lower cervical-supraclavicular region; or 4b. Stage PS IIA (LP or NS type) involving two or more lymph node regions above the dia phragm, with negative lymphangiogram and laparotomy. Subtotal lymphoid radiotherapy (mantle and spade fields); Waldeyer field also when upper cervical nodes involved. 5. StagePS IIA (LP or NS type)involving two or more lymph node regionsbelow thediaphragm,with negativespleen, liverand bone marrow atlaparotomy. Subtotal lymphoid radiotherapy only (full inverted"Vand mini mantle fields). 6. Any of the above with constitutional symptoms (fevern,ightsweatsand/or weightloss):StageslB or IIB. 7. As in4b, 5 or 6, but withone or two associateldocalizeedxtralymphatic site(so)f involvement:StagelIE"A or EB. Total ly mphoid radiotherapy only (mantle and full inverted-V fields; Waldeyer field also when upper cervical nodes involved). As in 4, 5 or 6, respectively, plus local irradiation of the extra lymphatic lesion(s); after a 6"8 week rest-periofdollowedby 6 cyclesof MOP combination chemotherapy (omittingpred nisone). 314 CA -A CANCER JOURNAL FOR CLINICIANS Table 9. (continued) Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) ClinicaSlituation 8. Any of the above with MC or LD type histology, 9. PS Illa"nAd lll5"(ALP or NS types). 10. PS Ill"A PS llI5"A (MC and LD types) and PS Ill"PBS III5("aBny type). 11. PS IV@.,."Aor B (any type) with biopsyproven liver involvement, 12. CS IVL"Aor B (any type) with multiple bilateral pulmonary lesions or pulmonary and biopsy proven pleural lesions. 13. CSIV PSIV andotherStagelV (A or B,anytype). Recommended Treatment Total lymphoid radiotherapy (mantle and full inverted"Vfields; Waldeyer field also when upper cervical node involved) alone or supplemented, after 6"8week rest period, with 6 cycles of MOP combina tion chemotherapy.1 6 Total lymphoid radiotherapy only (mantle and inverted-Vfields)i;nadditionwhen spleenisinvolvedeitherhepaticfieldirradi ation or 6 cycles of MOP chemotherapy. Totallymphoid radiotherapy(mantle,para aortic/hepatic, and pelvic fields) followed aftera 6"w8eek restperiodby 6 cyclesof MOP combination chemotherapy (omitting Prednisone). Split course therapy: 2"3cycles of MOPP combination chemotherapy, then para aortic/hepatic, mantle and pelvic field radiotherapy (sequence depending on rela tive extent of initial involvement), then after 8"12week rest period, 4"8more cycles of MOP chemotherapy (omitting Prednisone); alternatively, MOPP alone for 6"9cycles to documented remission, preferably supplemented by moderate dose radiotherapy to areas of initially bulky disease and 2"4consolidation cycles of MOP chemotherapy before optional main tenance chemotherapy (MOP every 2"3 months or VLB + CLB every month for 18"24months). MOPP combination chemotherapy (6"9 cycles), preferably followed by moderate dose (2,500"3,000 rads) radiotherapy to regions of initially bulky lymph node involvement in patients entering complete remission; consolidation and optional maintenance as in 11. As in 12, followed by consolidation and optio. nal maintenance chemotherapy as in 11. -J VOL 25, NO 6 NOVEMBER/DECEMBER1975 315 Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 10. Therapeutic Recommendationsfor PreviouslyTreated Patientsin Relapse (First Relapse) Clinical Situation Recommended Treatment 1. Recurrenceintreatedlymph node chain in patients previously treated with radio therapyonly. Low dose (2,000-2,500 rads 2 to 2 weeks) local radiotherapy plus 6 cycles of MOP combination chemotherapy. 2. Recurrence at margin of treated lymph node chain in patients previously treated with radiotherapy. Local radiotherapy, with dose limited to 2,000"2,500rads to previously irradiated area but carried to 4,000 rads/4 weeks to marginal recurrence; supplementary MOP chemotherapy optional. 3. Extension to previously untreated lymph node chainon same sideof diaphragm. High dose radiotherapy (4,000 rads/4 weeks) to newly involved chain and usually to all other previously unirradi ated lymphoid regions on both sides of diaphragm; supplementary MOP chemo therapy optional. 4. Extension to previously untreated lymph node chains on opposite side of diaphragm. (a) Extension from below diaphragm to cervical-supraclavicular nodes. (b) Exten sion from above diaphragm to para-aortic nodes. (a) Same as 3 above. (b) Laparotomy, if not previously done; if spleen or liver found to be involved, then as per 5 or 6, respectively; if nodes alone are involved and spleen removed, high dose radiotherapy to full inverted-V field; supplementary MOP chemotherapy indicated in presence of MC or LD histology or oesyBmptoms and optional in other histologies. 5. Extension to spleen, usually associated with para-aortic node involvement, in patients previously treated with radio therapy above diaphragm. Splenectomy with liver and bone marrow biopsies; if biopsies positive, then as per 6 or 7, respectively; if negative, high dose radio therapy to para-aortic/hepatic field (4400 rads-2200 rads/4 weeks),then to pelvic field (4400 rads/4 weeks); supplementary MOP chemotherapy with MC or LD histology or oesyBmptoms. 6. Biopsy-proven extension to liver, with or without evident lymph node disease, in patients previously treated with radio therapy only. Split course MOP chemotherapy (usually 3"4cycles initially), then low dose radio therapy (2,000 rads/3"4weeks) to the liver and regions of bulky lymphadenopathy, then 3-6 more cycles of MOP. @ E@t-' -.. .."-.,.@.ti-." 316 CA -A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 10 (continued) Clinical Situation Recommended Treatment 7. Biopsy-proven extension to bone marrow, with or without concurrent involvement of spleen and lymph nodes, in patients previously treated with radiotherapy only. MOP chemotherapy (6"9cycles), followed by 2-4 oeconsolidationcycles of MOP chemo therapy in patients attaining documented re mission; optional low dose (1,500"2,000 rads/ 2 weeks) radiotherapy to areas of bulky lymphadenopathy and optional maintenance chemotherapy as in Table 9., 11. 8. Solitary lesion in one lung in patients previously treated with radiotherapy only. 9. Multiple lesions in both lungs in patients previously treated with radiotherapy only. MOP chemotherapy (usually 6 cycles), supplemented by ipsilateral whole-lung irradiation (1,500 rads/3-4 weeks) with boost over involved area to 2,000-2,500 rads. MOP chemotherapy (6 or more cycles) and optional low dose radiotherapy to both lung fields (1,200"1,500 rads/4 weeks). 10. Apparently solitary extension to bone or subcutaneous tissues previously treated with radiotherapy only. Local radiotherapy (4,000 rads/4 weeks if region previously unirradiated; 1,500"2,000 rads/2 weeks plus MOP chemotherapy, 6 cycles, if region previously irradiated). 11. Multiple scattered osseous or subcutaneous lesions in patients previously treated with radiotherapy only. MOP chemotherapy (6"9cycles); optional low dose radiotherapy to sites of incomplete response. 12. In lymph node(s) in patients previously treated with single-drug chemotherapy only. Careful diagnostic evaluation and re-staging, then high dose, total lymphoid radio therapy if no extranodal disease is detected and hematologic tolerance is good; high dose local radiotherapy to involved areas plus 6 cycles of MOP chemotherapy is an acceptable alternative. 13. In extranodal site(s), such as bone marrow, liver, lungs, etc., in patients previously treated with single-drug chemotherapy only. 14. In patients previously treated with MOPP chemotherapy. MOPP, ABVD or CAVe chemotherapy, selecting combination with agents to which resistance has not yet been demonstrated. Renewed MOPP chemotherapy when first relapse occurs more than 12 months after first course of MOPP; for earlier relapses, oecrossovteoroth er drug combinations, such as ABVD or CAVe, when hematologic tolerance is good; palliative single-drug chemotherapy and/or local radiotherapy (for localized relapses) when hematologic tolerance is too poor to permit intensive chemotherapy. ,..,, .,,\ I@@ VOL 25 NO 6 NOVEMBER/DECEMBER 1975 317 11Therapeutic Table Recommendations for Previously Treated Patients In Relapse Relapses)MOP (Secondand Later toleranocreoptehremritsintensive combination chemotherapy when hematologic sites;locaal nd relapse involves multiple or extranodal or heavily irradiated radiotherapy when relapse involves local nodal or osseous site and hemato liongvoiclvetoslmerualnticpele is poor; single-drug, palliative chemotherapy when relapse ispoor. or extranodal or heavily irradiated sites and hematologic tolerance Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) velop oelaterelapses, more than 12 research aimed at the conquest of Stage months after completion of the last IV and other advanced disease states MOPP cycle, usually do well on another goes forward in major medical centers, course of MOPP; those relapsing earlier it is hoped that the judicious application are best regarded as MOPP failures and of the treatment principles and recom treated with one of the new oecrossover mendations set forth in this paper will combinations, such as ABVD or CAVe. help bring the benefits of modern ther Treatment options inevitably become apy and improved prognosis to all pa more and more severely restricted in pa tients with Hodgkin's disease. tients with multiple, sequential relapses (Table 11 .), due both to the limitations References on tissue tolerance imposed by prior therapy, and to the dwindling list of agents in which tumor resistance has not yet developed. Nonetheless, skillful use of the available options can give years of useful and productive life, even to the patient ultimately destined to die. Prognosis The dramatic improvement in the prognosis of Hodgkin's disease, which has resulted from the systematic applica tion of modern diagnostic and thera peutic advances, has been fully de scribed elsewhere,'7 and only a brief summary of our current data on survival and freedom from relapse, for all stages and for each separate stage, is presented here. (Table 12.) It should be noted that five-year survival is now high not only in Stages I and II, but in Stage III as well. The curve for relapse-free, 10-year survival flattens out at about 50 percent and represents a minimum estimate of the permanent cure rate which can now be achieved in Hodgkin's disease. As 1. Kaplan. H.S., and Rosenberg, S.A.: Extended field radical radiotherapy in advanced Hodgkin's disease: short-term results of 2 randomized clinical trials. Cancer Res. 26:1268-1276. 1966. 2. Kaplan, H.S., and Rosenberg. S.A.: Current status of clinical trials: Stanford experience. 19621972. Nat. Cancer Inst. Mongr. 36:363-371, 1973. 3. Rosenberg, S.A., and Kaplan, H.S.: The man agement of Stages I, II and III Hodgkin's disease with combined radiotherapy and chemotherapy. Cancer 35:55-63, 1975. 4. Lukes, Ri.; Craver, L.F.; Hall, T.C.. Rappaport, H., and Rubin, P.: Report of the no menclature committee. Cancer Res. 26:1311, 1966. 5. Kaplan, H.S.; Dorfman, R.F.; Nelsen, T.S., and Rosenberg, S.A.: Staging laparotomy and splenectomy in Hodgkin's disease: analysis of indi cations and patterns of involvement in 285 consec utive, unselected patients. Nat. Cancer Inst. Mon. ogr. 36:291-301, 1973. 6. Glatstein, E.; Trueblood, H.W.; Enright, L.P.; Rosenberg, S.A., and Kaplan, H.S.: Surgical stag ing of abdominal involvement in unselected patients with Hodgkin's disease. Radiology 97:425-432, 1970. 7. Carbone. PP.; Kaplan, H.S.; Musshoff, K.; Smithers, D.W., and Tubiana, M.: Report of the committee on Hodgkin's disease staging classifica tion. Cancer Res. 31: 1860-1861, 1971. 8. Page, V.; Gardner, A., and Karzmark, C.J.: Physical and dosimetric aspects of the radiotherapy of malignant lymphomas. I. The mantle technique. II. The inverted-V technique. Radiology 96:609- 626, 1970. 318 CA"A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on May 14, 2010 (American Cancer Society, Inc.) Table 12. Prognosis* Group 5-Year Survival(Percent) 5-Year Relapse-free(Percent) All stages, all cases Stage PS I (A & B) StagePS II(A & B) Stage PS III (A & B) Stage PS IV (A & B) 81.3 86.0 93.6 81.3 39.0 61.5 72.5 69.0 61.1 26.9 At 10 years, the curve for relapse-free survival has flattened out at about 50 percent, suggesting that at least half of all cases may now be permanently cured of their once inevitably fatal disease by meticulous diagnostic evaluation and staging, and the judicious selection and skillful administration of megavoltage radiotherapy and/or multi-agent combination chemotherapy. * Based on data from a series of 504 consecutive biopsy-proved, previously untreated patients with Hodgkin's disease routinely staged with lymphangiography and laparotomy with splenectomy, most of whom were treated with high dose, total lymphoid radio therapy in Stages IA, IB, IIA, lIB, and Il15A; total lymphoid radiation supplemented with either hepatic radiotherapy or MOPP chemotherapy in Stages lII5"Band IVH+A or B; and MOPP chemotherapy with or without supplementary radiotherapy in Stage IVM+A or B and IVLA or B. 9. Schultz. H.P.; Glatstein, E., and Kaplan. H.S.: Management of presumptive or proven Hodgkin's disease of the liver: description of a new radio therapy technique. In preparation. 10. Palos. B.: Kaplan, H.S., and Karzmark, Ci.: The use of thin lung shields to deliver limited whole-lung irradiation during mantle-field treatment of Hodgkin's disease. Radiology 101:441-442, 1971. 11. DeVita, VT.; Serpick. A.A., and Carbone, P.P.: Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann. Intern. Med. 73:881-895, 1970. 12. Nicholson, W.M. et al.: Combination chemo therapy in generalized Hodgkin's disease. Brit. Med. 1. 3:7-10. 1970. 13. Bonadonna, G.; Monfardini, S.; DeLena, M.; Uslenghi, C., and Zucali, R.: Adriamycin, bleomy cm, vinblastine and imidazole carboxamide (ABVD): a new combination effective in advanced Hodgkin's disease. Abst. XI Int'l. Cancer Con gress, Florence, Italy 1:271-272, 1974. 14. Rosenberg, S.A.: CCNU, adriamycin and vinblastine (CAVe) combination chemotherapy for advanced Hodgkin's disease. In preparation. 15. Castellino, R.A.; Glatstein, E.; Turbow, MM.; Rosenberg. S.. and Kaplan H.S.: Latent radiation injury of lungs or heart activated by steroid with drawal. Ann. Intern. Med. 80:593-599, 1974. 16. Moore, M.R.; Bull, i.M.; iones, SE.; Rosen berg, S.A., and Kaplan, H.S.: Sequential radio therapy and chemotherapy in the treatment of Hodgkin's disease. A progress report. Ann. Intern. Med. 77:1-9, 1972. 17. Kaplan, H.S.: Hodgkin's Disease. Cambridge, Mass. Harvard University Press, 1972. VOL 25, NO 6 NOVEMBER/DECEMBER 1975 319